Sex and rat strain determine sensitivity to kappa opioid-induced antinociception

Rationale: Recent studies indicate that sex and rodent strain are determinants of sensitivity to opioid-induced antinociception. Objectives: The present study examined the influence of sex and rat strain on K opioid-induced antinociception using a series of K opioids that vary in their relative effectiveness. Methods: In a warm-water (50, 52 and 55degreesC) tail-withdrawal procedure, the antinociceptive effects of K opioids were determined in male and female rats of the F344, Lewis and Sprague-Dawley (SD) strains. Results: In both males and females of each strain, spiradoline produced high levels of antinociception across all nociceptive stimulus intensities, whereas U50,488 produced high levels only at the low and moderate nociceptive stimulus intensities. Sex differences in the potency and effectiveness of these K opioids were relatively small and not consistently obtained. Enadoline, bremazocine and nalorphine were less effective than spiradoline in producing antinociception, and at low and moderate nociceptive stimulus intensities these opioids were both more potent and effective in F344 and SD males than their female counterparts. In contrast, in Lewis rats, only bremazoeine was more potent and effective in males. In combination tests, bremazocine shifted the spiradoline dose-effect curve leftward and/or upward in males and rightward in females (i.e., antagonized spiradoline). In contrast, in both males and females enadoline shifted the spiradoline dose-effect curve leftward and/or upward. Conclusions: These data indicate that K opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with V opioids, the magnitude of these sex differences was generally larger with the less effective K opioids and determined, in part, by rat strain and nociceptive stimulus intensity.